Abstract The use of electronic cigarettes (e-cigs) is increasing rapidly. Yet, little is known about the potential lung toxicity for inhaling e-cig aerosols relative to smoking. The FDA has deemed regulatory authority over e-cigs and needs data to determine how to regulate their designs and constituents. It is plausible that e-cig aerosol constituents (carriers, flavor, and byproducts of these) induce an inflammatory response in the lung, but there is no direct evidence for this, and what the magnitude of the effect is, if any. While there may be numerous ongoing laboratory in vitro and in vivo studies to assess e-cig exposure and toxicity, these utilize indirect methods for assessing lung toxicity. There also are ongoing human studies that focus on the effect of e-cig use on smoking- related biomarkers of exposure, but these usually assess biofluids outside the lung (e.g., blood and urine). It is unknown how any of these studies may relate to lung toxicity, e.g., the target organ, and thus there is a critical research gap. To assess human lung toxicity from e-cig use, we propose to conduct a clinical trial of 128 smokers to assess inflammatory responses in the lung via serial bronchoscopy. To do this, we will exploit an extraordinary opportunity for study e-cig toxicity by employing the new NIDIA standardized research e-cig (SREC). Subjects will be randomized to continued cigarette smoking (control), one of two e-cig use conditions (complete substitution with the nicotine SREC or dual use with planned smoking reduction), or complete substitution with nicotine replacement therapy (NRT). Each group will be 32 subjects and the trial will be 5 weeks (a 1 week run- in period, followed by 4 weeks of the experimental condition). Primary outcomes will be lung biomarkers (cell counts, cytokines, exhaled nitric oxide, RNA and microRNA gene expression, and untargeted metabolomics). Several biochemical measures to assess compliance will be employed. A biorepository of urine and nasal samples will be created for future studies to compare non-invasive biomarkers with lung biomarkers. The infrastructure for this trial is already established under an FDA- and IRB approved protocol. This study is significant because it will focus on lung inflammation, a plausible effect on the lungs of e-cig use, and the impact for switching to e-cigs or dual use, versus complete cessation with NRT. Such data are needed as soon as possible to assist the FDA in the regulation of e-cigs, including nicotine content. The study is innovative by using a clinical trial design using serial bronchoscopy, incorporating inflammation biomarkers with metabolomic and gene expression data, and uses an integrative, complementary and comprehensive approach through multiple ?omics assays (gene expression ? mRNA and miRNA, metabolomics, cell infiltrates and cytokine levels). This study has considerable public health impact because it will provide experimental evidence in humans of target organ effects.